MAN2C1-congenital disorder of deglycosylation 2

Mendelian MONDO:0030770 Pathograph 4 Show in embeddings browser congenital disorder of deglycosylation

MAN2C1-congenital disorder of deglycosylation 2 is an autosomal recessive free-oligosaccharide catabolism disorder caused by biallelic MAN2C1 variants. MAN2C1 encodes a cytosolic alpha-mannosidase that trims free oligosaccharides generated during N-glycosylation and glycoprotein degradation. Pathogenic variants cause accumulation and delayed processing of free oligosaccharides in patient-derived cells, producing a neurodevelopmental disorder with dysmorphic features, congenital anomalies including tongue hamartoma, intellectual disability, and brain anomalies such as polymicrogyria, interhemispheric cysts, hypothalamic hamartoma, callosal anomalies, and hypoplasia of the brainstem and cerebellar vermis.

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1
Inheritance
3
Pathophys.
3
Phenotypes
4
Pathograph
1
Genes
🏷

Classifications

👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Reported individuals have biallelic pathogenic MAN2C1 variants.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:35045343 SUPPORT Human Clinical
"six individuals, including two fetuses, with bi-allelic pathogenic variants in MAN2C1"
The initial cohort establishes biallelic MAN2C1 variants in affected individuals.
⚙

Pathophysiology

3
MAN2C1 cytosolic alpha-mannosidase deficiency
Biallelic MAN2C1 variants reduce cytosolic alpha-mannosidase activity required for processing free oligosaccharides.
MAN2C1 hgnc:6827
oligosaccharide catabolic process GO:0009313 ↓ DECREASED
alpha-mannosidase activity GO:0004559 ↓ DECREASED
Downstream
Free oligosaccharide processing delay and accumulation MAN2C1 deficiency delays cytosolic free oligosaccharide trimming and causes free oligosaccharide accumulation in patient cells.
Show evidence (1 reference)
PMID:35045343 SUPPORT Human Clinical
"The catabolism of fOSs has been linked to the activity of a specific cytosolic mannosidase, MAN2C1"
The study identifies MAN2C1 as the cytosolic mannosidase in free oligosaccharide catabolism.
Free oligosaccharide processing delay and accumulation
Accumulated free oligosaccharides disrupt glycan turnover homeostasis and are associated with abnormal neurodevelopment.
oligosaccharide catabolic process GO:0009313 ↓ DECREASED
Downstream
Neurodevelopmental malformation and cognitive phenotype Free-oligosaccharide catabolism failure is associated with intellectual disability and structural brain anomalies.
Show evidence (1 reference)
PMID:35045343 SUPPORT In Vitro
"Complementation experiments with isogenic MAN2C1-KO HAP1 cells confirm the pathogenicity of three of the identified MAN2C1 variants."
Complementation experiments support pathogenicity of MAN2C1 variants in a cellular model.
Neurodevelopmental malformation and cognitive phenotype
The clinical phenotype includes intellectual disability and structural brain anomalies, including polymicrogyria and callosal abnormalities.
Show evidence (1 reference)
PMID:35045343 SUPPORT Human Clinical
"These individuals exhibit dysmorphic facial features, congenital anomalies such as tongue hamartoma, variable degrees of intellectual disability, and brain anomalies including polymicrogyria, interhemispheric cysts, hypothalamic hamartoma, callosal anomalies, and hypoplasia of brainstem and..."
The initial cohort directly describes the neurodevelopmental and congenital-anomaly phenotype.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for MAN2C1-congenital disorder of deglycosylation 2 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

3
Intellectual disability HP:0001249
Show evidence (1 reference)
PMID:35045343 SUPPORT Human Clinical
"variable degrees of intellectual disability"
The cohort directly reports intellectual disability.
Polymicrogyria HP:0002126
Show evidence (1 reference)
PMID:35045343 SUPPORT Human Clinical
"brain anomalies including polymicrogyria"
The cohort directly reports polymicrogyria.
Callosal anomalies HP:0001273
Show evidence (1 reference)
PMID:35045343 SUPPORT Human Clinical
"callosal anomalies"
The cohort directly reports callosal anomalies.
🧬

Genetic Associations

1
MAN2C1 (Biallelic pathogenic variants)
Gene: MAN2C1 hgnc:6827 relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:35045343 SUPPORT Human Clinical
"six individuals, including two fetuses, with bi-allelic pathogenic variants in MAN2C1"
The initial cohort establishes MAN2C1 as the causal gene.
{ }

Source YAML

click to show 
name: MAN2C1-congenital disorder of deglycosylation 2
creation_date: "2026-07-06T06:04:18Z"
description: >-
  MAN2C1-congenital disorder of deglycosylation 2 is an autosomal recessive
  free-oligosaccharide catabolism disorder caused by biallelic MAN2C1 variants.
  MAN2C1 encodes a cytosolic alpha-mannosidase that trims free oligosaccharides
  generated during N-glycosylation and glycoprotein degradation. Pathogenic
  variants cause accumulation and delayed processing of free oligosaccharides in
  patient-derived cells, producing a neurodevelopmental disorder with
  dysmorphic features, congenital anomalies including tongue hamartoma,
  intellectual disability, and brain anomalies such as polymicrogyria,
  interhemispheric cysts, hypothalamic hamartoma, callosal anomalies, and
  hypoplasia of the brainstem and cerebellar vermis.
category: Mendelian
disease_term:
  preferred_term: congenital disorder of deglycosylation 2
  term:
    id: MONDO:0030770
    label: congenital disorder of deglycosylation 2
synonyms:
- CDDG2
- MAN2C1 deficiency
parents:
- congenital disorder of deglycosylation
classifications:
  icimd_category:
  - classification_value: other_glycan_metabolism
    notes: >-
      The local ICIMD enum folds the specific deglycosylation subgroup into the
      broader other_glycan_metabolism value.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Reported individuals have biallelic pathogenic MAN2C1 variants.
  evidence:
  - reference: PMID:35045343
    reference_title: "Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      six individuals, including two fetuses, with bi-allelic pathogenic variants
      in MAN2C1
    explanation: >-
      The initial cohort establishes biallelic MAN2C1 variants in affected
      individuals.
pathophysiology:
- name: MAN2C1 cytosolic alpha-mannosidase deficiency
  description: >-
    Biallelic MAN2C1 variants reduce cytosolic alpha-mannosidase activity
    required for processing free oligosaccharides.
  role: trigger
  genes:
  - preferred_term: MAN2C1
    term:
      id: hgnc:6827
      label: MAN2C1
  molecular_functions:
  - preferred_term: alpha-mannosidase activity
    modifier: DECREASED
    term:
      id: GO:0004559
      label: alpha-mannosidase activity
  biological_processes:
  - preferred_term: oligosaccharide catabolic process
    modifier: DECREASED
    term:
      id: GO:0009313
      label: oligosaccharide catabolic process
  chemical_entities:
  - preferred_term: free oligosaccharide
    modifier: INCREASED
    term:
      id: CHEBI:50699
      label: oligosaccharide
  evidence:
  - reference: PMID:35045343
    reference_title: "Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The catabolism of fOSs has been linked to the activity of a specific
      cytosolic mannosidase, MAN2C1
    explanation: >-
      The study identifies MAN2C1 as the cytosolic mannosidase in free
      oligosaccharide catabolism.
  downstream:
  - target: Free oligosaccharide processing delay and accumulation
    description: >-
      MAN2C1 deficiency delays cytosolic free oligosaccharide trimming and causes
      free oligosaccharide accumulation in patient cells.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35045343
      reference_title: "Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        MAN2C1 variants lead to accumulation and delay in the processing of fOSs
        in proband-derived cells.
      explanation: >-
        Patient-cell experiments directly support the accumulated free
        oligosaccharide node.
- name: Free oligosaccharide processing delay and accumulation
  description: >-
    Accumulated free oligosaccharides disrupt glycan turnover homeostasis and
    are associated with abnormal neurodevelopment.
  role: central_effector
  biological_processes:
  - preferred_term: oligosaccharide catabolic process
    modifier: DECREASED
    term:
      id: GO:0009313
      label: oligosaccharide catabolic process
  chemical_entities:
  - preferred_term: free oligosaccharide
    modifier: INCREASED
    term:
      id: CHEBI:50699
      label: oligosaccharide
  evidence:
  - reference: PMID:35045343
    reference_title: "Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Complementation experiments with isogenic MAN2C1-KO HAP1 cells confirm the
      pathogenicity of three of the identified MAN2C1 variants.
    explanation: >-
      Complementation experiments support pathogenicity of MAN2C1 variants in a
      cellular model.
  downstream:
  - target: Neurodevelopmental malformation and cognitive phenotype
    description: >-
      Free-oligosaccharide catabolism failure is associated with intellectual
      disability and structural brain anomalies.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Neurodevelopmental malformation and cognitive phenotype
  description: >-
    The clinical phenotype includes intellectual disability and structural brain
    anomalies, including polymicrogyria and callosal abnormalities.
  role: consequence
  evidence:
  - reference: PMID:35045343
    reference_title: "Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These individuals exhibit dysmorphic facial features, congenital anomalies
      such as tongue hamartoma, variable degrees of intellectual disability, and
      brain anomalies including polymicrogyria, interhemispheric cysts,
      hypothalamic hamartoma, callosal anomalies, and hypoplasia of brainstem
      and cerebellar vermis.
    explanation: >-
      The initial cohort directly describes the neurodevelopmental and
      congenital-anomaly phenotype.
phenotypes:
- name: Intellectual disability
  description: Intellectual disability is reported with variable severity.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:35045343
    reference_title: "Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      variable degrees of intellectual disability
    explanation: The cohort directly reports intellectual disability.
- name: Polymicrogyria
  description: Polymicrogyria is among the reported brain anomalies.
  phenotype_term:
    preferred_term: Polymicrogyria
    term:
      id: HP:0002126
      label: Polymicrogyria
  evidence:
  - reference: PMID:35045343
    reference_title: "Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      brain anomalies including polymicrogyria
    explanation: The cohort directly reports polymicrogyria.
- name: Callosal anomalies
  description: Corpus callosum anomalies are reported among structural brain findings.
  phenotype_term:
    preferred_term: Abnormal corpus callosum morphology
    term:
      id: HP:0001273
      label: Abnormal corpus callosum morphology
  evidence:
  - reference: PMID:35045343
    reference_title: "Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      callosal anomalies
    explanation: The cohort directly reports callosal anomalies.
genetic:
- name: MAN2C1
  association: Biallelic pathogenic variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: MAN2C1
    term:
      id: hgnc:6827
      label: MAN2C1
  evidence:
  - reference: PMID:35045343
    reference_title: "Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      six individuals, including two fetuses, with bi-allelic pathogenic variants
      in MAN2C1
    explanation: The initial cohort establishes MAN2C1 as the causal gene.